Title Comparative effectiveness of HMA with venetoclax versus intensive chemotherapy in AML with very-high-risk cytogenetics
Authors Aguirre, Luis E ; Bewersdorf, Jan Philipp ; Liu, Yiwen ; Shallis, Rory M ; Boussi, Leora ; Žučenka, Andrius ; Garciaz, Sylvain ; Bystrom, Rebecca P ; DeAngelo, Daniel J ; Stone, Richard M ; Luskin, Marlise R ; Garcia, Jacqueline S ; Winer, Eric S ; Ling, Kelly ; Chen, Evan C ; Wadleigh, Martha ; Berton, Guillaume ; Stein, Eytan M ; Goldberg, Aaron D ; Mendez, Lourdes ; Zeidan, Amer M ; Sallman, David A ; Shimony, Shai ; Stahl, Maximilian
DOI 10.1016/j.bneo.2026.100201
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Is Part of Blood neoplasia.. American Society of Hematology; Elsevier Inc.. 2026, In Press, Journal Pre-proof, art. no. 100201, p. [1-30].. eISSN 2950-3280
Keywords [eng] AML ; very-high-risk cytogenetics ; HMA+venetoclax ; intensive chemotherapy ; complete remission ; allogeneic stem cell transplant ; monosomal karyotype ; complex karyotype ; inv(3)/t(3 ; 3)
Abstract [eng] The optimal frontline therapy for acute myeloid leukemia (AML) with very-high-risk cytogenetics (vHRC)—defined by complex karyotype (CK), monosomal karyotype (MK), or inv(3)/t(3;3)—remains uncertain. We retrospectively analyzed 358 newly diagnosed AML-vHRC cases treated at five academic centers (2014–2024), stratified by intensive chemotherapy (IC) versus hypomethylating agent plus venetoclax (HMA+ven). Cytogenetic features included CK in 90.2%, MK in 64%, and inv(3)/t(3;3) in 9.8%; TP53 mutations occurred in 51%. Frontline therapy was IC in 40% and HMA+ven in 60%, with a median age of 67 years (range, 22–92). Median overall survival (OS) for AML-vHRC was 8 months compared with 31 months for non-vHRC AML (p<0.0001). Composite complete remission (cCR) rates were similar with IC versus HMA+ven (55% vs 54%, p=0.91). Patients with inv(3)/t(3;3) had inferior responses (cCR 36%) compared with CK/MK-AML (67%; p<0.001). No OS differences by frontline regimen were observed among patients aged 60–75 years (7.7 vs 6.6 months, p=0.43), those with TP53-mutated disease (8.1 vs 5.8 months, p=0.17), or following alloHSCT (35 vs 25 months, p=0.56). On multivariable analysis, older age (HR 1.02, p=0.0003), inv(3)/t(3;3) (HR 2.12, p=0.0002), and TP53mt (HR 2.07, p<0.0001) independently predicted inferior OS, whereas alloHSCT improved OS (HR 0.42, p<0.0001); frontline regimen (HMA+ven vs IC) was not associated with OS (HR 0.84, p=0.2814). In AML-vHRC, IC and HMA+ven yield comparable remission and survival outcomes. Given equivalent efficacy and similar early mortality, HMA+ven represents a reasonable frontline option for patients aged 60–75 years, those with TP53mt disease, and patients intended for alloHSCT.
Published American Society of Hematology; Elsevier Inc
Type Journal article
Language English
Publication date 2026
CC license CC license description